The present invention is related to the combination of a non-steroidal antiinflammatory drug (xe2x80x9cNSAIDxe2x80x9d) or one of its single enantiomers or salt of the NSAID, and a proton pump inhibitor or one of its single enantiomers, or an alkaline salt of the proton pump inhibitor or one of its single enantiomers, in a single oral pharmaceutical dosage form.
Although NSAIDs are often used for their antiinflammatory, analgesic, and/or antipyretic effects, it is well known that NSAIDs have the potential to cause gastrointestinal (GI) bleeding through a variety of mechanisms related to their topical and systemic effects. The GI bleeding may depend on the length of the treatment and on the particular drug. This problem is important in cases where the therapy must be continued for a long period of time. For example, osteoarthritis and rheumatoid arthritis in the elderly is often treated with long-term NSAID therapy, as chronic treatment is needed to control pain and inflammation and to improve quality of life.
Additionally it is well known that because of their side-effects on the GI tract, NSAIDs are invariably administered after meals or, generally, when the stomach is not empty. This pharmacological principle is confirmed by the recommendations found in the labeling of these medications. Patients who have an ulcer or who are susceptible to developing ulcers are commonly advised to avoid taking NSAIDs for pain, inflammation, and/or fever.
Other measures which can be taken to decrease GI side affects associated with NSAID therapy is to coadminister an H2 blocker e.g. ranitidine, or a prostaglandin analogue, e.g. misoprostol, with the NSAID. In fact, a combination tablet containing diclofenac sodium and misoprostol (Arthrotec(copyright), Pharmacia Corp.) has had FDA approval since 1988.
There is a continuing need for analgesic medications able to provide high efficacy pain relief while reducing the possibility of undesirable effects. Non-steroidal anti-inflammatory drugs, including compounds such as ibuprofen, ketoprofen and diclofenac, have anti-inflammatory actions and are effective on pain associated with the release of prostaglandins and other mediators of inflammation. For example, diclofenac and pharmaceutically acceptable salts thereof, e.g. diclofenac sodium, are considered to be extremely potent and effective as an analgesic and anti-inflammatory agent. Diclofenac is approved in the United States for the long-term symptomatic treatnent of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is also considered to be useful for the short-term treatment of acute musculoskeletal injury, acute shoulder pain, postoperative pain and dysmenorrhea. However, NSAIDs such as diclofenac produce side effects in about 20% of patients that require cessation of medication. Side effects include, for example, gastrointestinal bleeding and the abnormal elevation of liver enzymes.
Non-steroidal anti-inflammatory drugs (NSAIDs) exert most of their anti-inflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Inhibition of COX-1 causes a number of side effects including inhibition of platelet aggregation associated with disorders of coagulation, and gastrointestinal side effects with the possibility of ulcerations and of hemorrhage. It is believed that the gastrointestinal side effects are due to a decrease in the biosynthesis of prostaglandins which are cytoprotective of the gastric mucosa.
A high incidence of side effects has historically been associated with chronic use of classic cyclooxygenase inhibitors, all of which are about equipotent for COX-1 or COX-2, or which are COX-1-selective. While renal toxicity occurs, it usuallybecomes evident in patients who already exhibit renal insufficiency (D. Kleinknecht, Sem. Nephrol. 15: 228, 1995). By far, the most prevalent and morbid toxicity is gastrointestinal. Even with relatively nontoxic drugs such as piroxicam, up to 4% of patients experience gross bleeding and ulceration (M.J.S. Langman et al, Lancet 343: 1075, 1994). In the United States, it is estimated that some 2000 patients with rheumatoid arthritis and 20,000 patients with osteoarthritis die each year due to gastrointestinal side effects related to the use of COX inhibitors. In the UK, about 30% of the annual 4000 peptic ulcer-related deaths are attributable to COX inhibitors (Scrip 2162, p.17). COX inhibitors cause gastrointestinal and renal toxicity due to the inhibition of synthesis of homeostatic prostaglandins responsible for epithelial mucus production and renal blood flow, respectively.
The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxins, hormones, cytokines and growth factors. It has been proposed that COX-2 is mainly responsible for the pathological effects of prostaglandins, which arise when rapid induction of COX-2 occurs in response to such agents as inflanmmatory agents, hormones, growth factors, and cytokines. Selective inhibitors of COX-2 have anti-inflammatory, antipyretic and analgesic properties similar to those of a conventional non-steroidal anti-inflammatory drug (NSAID), but COX-2 inhibitors have been touted as providing a reduced potential for gastrointestinal toxicity, among other side effects. Nevertheless, experience with selective COX-2 inhibitors is limited relative to experience with non-selective COX inhibitors (which non-selectively inhibit COX-1 and COX-2). Non-selective COX inhibitors are widely used, and it is expected that these drugs will continue to be widely used. Further, there has been recent suggestions that COX-2 inhibitors have serious but previously unrecognized side effects, including increased intraocular pressure and the risk of glaucoma, as well as possible effects on the central nervous system.
For years, neutralization of gastric acid with antacids was the only relief from the pain of ulcers. However, more recently, a class of antisecretory agents that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by the specific inhibition of the H+, K+xe2x80x94ATPase enzyme system at the secretory surface of the gastric parietal cell, has been developed. These agents (hereinafter xe2x80x9cproton pump inhibitorsxe2x80x9d) provide a more specific class of inhibitors of gastric acid secretion in mammals and man by blocking the final step of acid production.
Generally, proton pump inhibitors, their single enantiomers or alkaline salts thereof, are used for the prevention and treatment of gastric acid related diseases including, but not limited to, reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. These proton pump inhibitors may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent acid aspiration of gastric acid and to prevent and treat stress ulceration. Also, they may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these. Additionally, these proton pump inhibitors may be used for the treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable, such as patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, in patients with gastrinomas, and in particular in patients on NSAID therapy.
U.S. Pat. No. 5,817,338 (Bergstrand, et al.) describes multiple unit tableted dosage forms of omeprazole, a proton pump inhibitor commercially available for inhibiting gastric acid secretion in humans. Therein, it is suggested that omeprazole may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable, e.g., in patients on NSAID therapy. However, this patent does not describe pharmaceutical formulations combining a proton pump inhibitor such as omeprazole with an NSAID.
It is an object of this invention to provide a method for the treatment of pain, inflammation, and/or fever with the use of a NSAID without the undesirable stomach discomfort and other side effects typically associated with NSAID therapy.
It is a further object of the invention to decrease the risk of the development and/or exacerbation of ulcers which may occur during NSAID therapy.
It is a further object of the invention to promote patient compliance and thereby increase efficacy of NSAID treatment in patients who are being chronically treated with NSAIDs.
It is a further object of the invention to provide prophylactic treatment to a human patient who is on NSAID therapy or is about to begin NSAID therapy, in order to avoid or minimize gastrointestinal side-effects.
It is a further object of the invention to provide prophylactic treatment to a human patient who is on a therapy known to have significant gastrointestinal side effects or is about to begin such a therapy, in order to avoid or e such side effects.
It is a further object of the invention to provide cost effective therapy to decrease the risk of the development and/or exacerbation of ulcers which may occur during NSAID therapy.
In view of the above-mentioned objects and others, the invention is directed to an oral solid dosage form comprising a therapeutically effective amount of an NSAID and a proton pump inhibitor in an amount effective to inhibit or prevent gastrointestinal side effects normally associated with the NSAID treatment.
The invention is further directed to a solid oral dosage form comprising
a) an NSAID (e.g. diclofenac or a pharmaceutically acceptable salt thereof) extended release tablet and
b) an enterically coated proton-pump inhibitor without a separating layer between the proton pump inhibitor and the enteric coat.
The invention is further directed to a (non-steroidal) antiinflammatory, analgesic, and antipyretic oral therapy which does not possess any substantial gastrointestinal side-effects, comprising an orally administrable dosage form comprising a therapeutically effective amount of an NSAID and an amount of a proton pump inhibitor effective to substantially inhibit gastrointestinal side effects of the NSAID, together with one or more pharmaceutically acceptable excipients.
The invention is further directed to a dosage form comprising a therapeutically effective amount of an NSAID and an amount of a proton pump inhibitor effective to substantially inhibit gastrointestinal side effects of the NSAID, wherein said proton pump inhibitor is coated with a material suitable to prevent contact of said proton pump inhibitor with acidic gastric juice (e.g. an enteric coating). In preferred embodiments, the material is directly coated onto the proton pump inhibitor without a separating layer between the material and the proton pump inhibitor.
The invention is further directed to the prophylactic treatment of a human patient who is on NSAID therapy or is about to begin NSAID therapy, via the concurrent administration of a proton pump inhibitor.
The invention is further directed to the prophylactic treatment of a human patient who is on a therapy known to have significant gastrointestinal side effects or is about to begin such a therapy, via the concurrent administration of a proton pump inhibitor.
The invention is further related to a method of treating a human patient in need of antiinflammatory, analgesic and/or antipyretic therapy, comprising orally administering to the patient an oral pharmaceutical dosage form comprising a therapeutically effective amount of an NSAID and an amount of a proton pump inhibitor effective to substantially inhibit gastrointestinal side effects of the NSAID.
In certain preferred embodiments, the dosage form is an oral tablet comprising the NSAID, the proton pump inhibitor, and one or more pharmaceutically acceptable excipients. In other preferred embodiments, the NSAID and the proton pump inhibitor comprise a mixture of tablets, powders, pellets, granules, or inert nonpareil beads coated with the drugs, contained within a gelatin capsule.
The inventive formulations and methods described herein promote patient compliance and thereby increase efficacy of NSAID treatment in patients who are being chronically treated with NSAIDs. In other words, the inventive formulations increase the likelihood that a patient on NSAID therapy who is noncompliant due to gastrointestinal side effects, or who forgets or refuses to take both medications separately will be more accepting of a single composition combining the NSAID and proton pump inhibitor, particularly due to the avoidance of gastrointestinal side effects.
Proton pump inhibitors are known to be highly acid labile, and therefore it is preferred that the proton pump inhibitor(s) contained in the dosage forms of the invention be protected from contact with acidic gastric juice.
In certain preferred embodiments, the proton pump inhibitor is omeprazole.
In certain preferred embodiments, the NSAID is diclofenac, more preferably diclofenac sodium.
For purposes of this disclosure, all references to proton pump inhibitors and NSAIDs include their single enantiomers and their pharmaceutically acceptable salts.
For purposes of this disclosure, the phrase xe2x80x9csubstratesxe2x80x9d is meant to encompass inert pharmaceutically acceptable beads, particles, granules or pellets.
For purposes of this disclosure, the phrase xe2x80x9ccombination pharmaceuticalxe2x80x9d shall be understood to include any drug composition containing at least two therapeutically active components of which at least one is a non-steroidal antiinflammatory drug. The term xe2x80x9cpain-alleviatingxe2x80x9d shall be understood herein to include the expressions xe2x80x9cpain-suppressingxe2x80x9d and xe2x80x9cpain-inhibitingxe2x80x9d as the invention is applicable to the alleviation of existing pain as well as the suppression or inhibition of pain which would otherwise ensue from an imminent pain-causing event.